The present invention relates to a process for obtaining N-monosubstituted amides, which are useful as synthetic intermediates in practically all branches of organic chemistry, and many of which are also important as compounds possessing biological and physiological activity, including a physiological cooling effect for cosmetics, flavorings and other applications.
Among numerous known methods for obtaining N-monosubstituted amides, the Ritter reaction has long been considered to be one of the simplest processes based on readily available reagents, e.g., nitrites, sulfuric acid, olefins, alcohols, aldehydes, and/or other potential donors of a carbenium ion.
In their original experiments, Ritter and coworkers added olefins to a mixture of sulfuric acid and acetonitrile in glacial acetic acid as a solvent and, after a simple workup, obtained N-monosubstituted amides in relatively good yields (J. J. Ritter and P. P. Minieri, J. Amer. Chem. Soc., 1948, Vol. 70, pp. 4045-4048). In a number of following publications, they also used tertiary and secondary alcohols as donors of a carbenium ion, and found that secondary alcohols required harsher conditions, e.g., concentrated sulfuric acid as the reaction medium instead of dilution with acetic acid (J. J. Ritter and J. Kalish, J. Amer. Chem. Soc., 1948, Vol. 70, pp. 4048-4049; F. R. Benson and J. J. Ritter, ibid., 1949, Vol. 71, pp. 4128-4129). It was found that primary alcohols did not react, even under harsher reaction conditions. In fact, as stated in the latter reference, xe2x80x9cEfforts to utilize a primary alcohol in the reaction proved fruitless; expedients such as the use of elevated temperatures, prolonged heating or the employment of fuming sulfuric acid were unsuccessful in the production of N-primary alkyl amides.xe2x80x9d
Certain limited exceptions to that general rule have been reported. See, for example, Table 1. In all cases, an excess of nitrile has been used with respect to the alcohol.
The occurrence of very poor yields of amide formation, or even a total inability of methanol and other lower primary alcohols to take part in the xe2x80x9cclassicxe2x80x9d Ritter reaction has frequently been confirmed in later publications and reviews. See, for example: D. H. R. Barton et al., J. Chem. Soc. Perkin I, 1974, pp. 2101-2107; T. Kiersznicki and R. Mazurkiewicz, Rocz. Chem., 1977, Vol. 51, pp.1021-1026; A. G. Martinez et al., Tetrahedron Lett., 1989, Vol. 30, pp. 581-582; R. Bishop, Ritter-type Reactions. In: Comprehensive Organic Synthesis, eds. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, Vol. 6, pp. 261-300; H. Firouzabadi et al., Synth. Commun., 1994, Vol. 24, pp. 601-607; and H. G. Chen et al., Tetrahedron Lett., 1996, Vol 37, pp. 8129-8132, each of which are incorporated by reference.
Several xe2x80x9cnon-classicxe2x80x9d Ritter reaction modifications have been developed in order to attempt to obtain N-primary alkyl amides. For instance, n-decanol (0.95 mmol) and acetonitrile (96 mmol) in the presence of 3.4 mmole of dichloro(phenyl)methylium hexachloroantimonate gave N-decylacetamide in 60% yield (D. H. R. Barton et al., J. C. S. Perkin I, 1974, pp. 2101-2107). Similarly, the addition of 10 mmoles of ethanol or butanol to a mixture of 10 mmoles of trifluoromethanesulfonic anhydride and a double excess of acetonitrile or benzonitrile gave 80-90% yield of the corresponding N-alkylamides (A. G. Martinez et al., Tetrahedron Lett., 1989, Vol. 30, pp. 581-582). However, use of such xe2x80x9cexoticxe2x80x9d and costly reagents as these, makes these modifications industrially impractical.
Patents relating to processes for obtaining N-hydrocarbyl substituted amides include U.S. Pat. No. 5,811,580; EP846,678 A1; and U.S. Pat. No. 5,712,413.
Finally, an article describing clay (Montmorillonite KSF) catalyzed amidation of alcohols, a primary aliphatic alcohol n-octanol was reported inactive (H. M. Sampar Kumar et al., New J. Chem., 1999, Vol. 23, pp. 955-956).
Thus, it is clear that the need still exists for an economically feasible and practical method for obtaining N-monosubstituted amides by a Ritter type reaction of nitrites with primary aliphatic alcohols or other compounds containing primary alkoxy groups.
Among other aspects, the present invention relates to the surprising discovery of an improved process for obtaining N-primary alkyl monosubstituted amides, cyclic amides or lactams, functionally substituted diamides and polyamides, and cyclic polyamides using relatively inexpensive and readily available reagents including nitrites, acids and primary alkoxy compounds such as lower primary alkohols.
In one embodiment, the present invention relates to a process for obtaining an amide of the general formula Rxe2x80x94(CO)xe2x80x94NHxe2x80x94CH2xe2x80x94X, said process comprising contacting a nitrile of the general formula Rxe2x80x94CN with:
a) an acid; and
b) an alkoxy-containing compound comprising at least one alkoxy functionality of the general formula xe2x80x94OCH2xe2x80x94X;
wherein R is hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, which substituents can be substituted or unsubstituted; wherein X is hydrogen or a radical having the general formula xe2x80x94CHR1R2; and wherein R1 and R2 independently or collectively represent hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, or any combination thereof, which substituents can be substituted or unsubstituted.
In addition, the process of the present invention comprises reacting at least one nitrile with a reagent comprising both (i) at least one suitable alkoxy functionality; and (ii) at least one suitable acid functionality.
For example, the present invention includes a process for obtaining an amide of the general formula Rxe2x80x94(CO)xe2x80x94NHxe2x80x94CH2xe2x80x94X, said process comprising contacting a nitrile of the general formula Rxe2x80x94CN with a monoalkylsulfate of the general formula Xxe2x80x94CH2xe2x80x94Oxe2x88x92SO3 H, wherein R is again selected from hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, which substituent can be substituted or unsubstituted; and wherein X is selected from hydrogen or a radical having the general formula xe2x80x94CHR1R2, wherein R1 and R2 individually or collectively represent hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, or any combination thereof, and which substituents can again be substituted or unsubstituted.
In another example, the present invention provides a process for obtaining an amide of the general formula Rxe2x80x94(CO)xe2x80x94NHxe2x80x94CH2xe2x80x94X, said process comprising contacting a nitrile of the general formula Rxe2x80x94CN with one or more acid phosphates, e.g., monoalkyl phosphates; dialkyl phosphates; mono, di, and trialkyl pyrophosphates; and mono-, di-, tri, and polyalkyl polyphosphates and the like, comprising at least one alkoxy functionality of the generic formula XCH2xe2x80x94Oxe2x80x94 and one or more acid phosphate functionalities of the generic formula: 
Additional advantages and embodiments of the invention will be obvious from the description, or may be learned by practice of the invention. Further advantages of the invention will also be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. Thus, it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory of certain embodiments of the invention, and are therefore not restrictive of the invention as claimed.
The present invention may be understood more readily by reference to the following detailed description, including any figures, tables and examples provided herein. It is also to be understood that this invention is not limited to the specific embodiments and methods described below, as specific components and/or conditions may, of course, vary. Furthermore, the terminology used herein is used only for the purpose of describing particular embodiments of the present invention and is not intended to be limiting in any way.
It must also be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9caxe2x80x9d, xe2x80x9canxe2x80x9d, and xe2x80x9cthexe2x80x9d comprise plural referents unless the context clearly dictates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.
Ranges may be expressed herein as from xe2x80x9caboutxe2x80x9d or xe2x80x9capproximatelyxe2x80x9d one particular value and/or to xe2x80x9caboutxe2x80x9d or xe2x80x9capproximatelyxe2x80x9d another particular value. When such a range is expressed, another embodiment comprises from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent xe2x80x9caboutxe2x80x9d or xe2x80x9capproximately,xe2x80x9d it will be understood that the particular value forms another embodiment.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a branched or unbranched, cyclic or acyclic saturated hydrocarbon group, including without limitation, such examples as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclohexyl, p-menthyl, octyl, eicosyl, tetracosyl and the like.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to a hydrocarbon group bound to an organic or inorganic molecule through an xe2x80x9cxe2x80x94Oxe2x80x94xe2x80x9d ether linkage. For example, as used herein, an xe2x80x9calkoxyxe2x80x9d group may be defined as xe2x80x94OR wherein R represents an alkyl group.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a hydrocarbon group containing at least one double bond.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a hydrocarbon group containing at least one triple bond.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a hydrocarbon group having the ring structure characteristic of benzene, naphthalene, and anthracene; i.e., a hydrocarbon group having either the aromatic six carbon ring of benzene or the fused six carbon rings of the other aromatic derivatives. For example, an aryl group as used herein may include, without limitation, a phenyl C6H5 or naphthyl C10H7 group.
The terms xe2x80x9cheterocyclexe2x80x9d and/or xe2x80x9cheterocyclic,xe2x80x9d as used herein, designate a closed ring structure, usually of five, six, or seven members, in which one or more of the atoms in the ring is a heteroatom such as sulfur, nitrogen, oxygen, and the like. Suitable examples include, without limitation, pyridine, pyrrole, furan, thiophene, tetrahydrofuran, and piperidine.
The term xe2x80x9cfunctionally substituted,xe2x80x9d as used herein, means that the group or moiety of concern contains one or more functional groups (functional substituents) or any other heteroatomic groups. Such examples include, without limitation, carbonyl group(s), hydroxy groups, cyano groups, alkoxy groups, carboxy group(s), alkoxycarbonyl group(s), amino group(s), nitro group(s), nitroso group(s), halogen group(s) (e.g., chloro, fluoro or bromo groups), siloxy group(s), and the like.
As used herein with respect to any particular chemical formula, xe2x80x9cMexe2x80x9d refers to a methyl group, xe2x80x9cEtxe2x80x9d refers to an ethyl group, xe2x80x9cBuxe2x80x9d refers to a butyl group, and xe2x80x9cPhxe2x80x9d refers to a phenyl group.
The present invention relates to a process for obtaining N-monosubstituted amides, cyclic amides or lactams, functionally substituted diamides and polyamides, and cyclic polyamides. To this end, contrary to the teachings of the prior art, it has been discovered that these amides can be obtained by reacting two or more reagents which independently or collectively provide at least one nitrile functionality, at least one alkoxy functionality, and at least one suitable acid functionality, in an environment suitable for amide formation.
In a first aspect, the present invention provides a process for obtaining N-monosubstituted amides having the generic formula (I):
Rxe2x80x94COxe2x80x94NHxe2x80x94CH2Xxe2x80x83xe2x80x83(I)
wherein R is a hydrogen or any alkyl, cycloalkyl, alkenyl,,cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, which substituent can be substituted or unsubstituted, and wherein X is a hydrogen or a radical having the general formula xe2x80x94CHR1R2 wherein R1 and R2 independently or collectively represent hydrogens or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent(s), or any combination thereof, which substituent(s) can also be functionally substituted or unsubstituted.
In one embodiment, the process comprises reacting: (1) at least one nitrile having the generic formula (II):
Rxe2x80x94CNxe2x80x83xe2x80x83(II)
wherein R is a hydrogen or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, which substituents can be substituted or unsubstituted; with (2) at least one alkoxy compound comprising at least one suitable alkoxy functionality of the generic formula (III):
xe2x80x94Oxe2x80x94CH2xe2x80x94Xxe2x80x83xe2x80x83(III)
wherein X is a hydrogen or a radical having the general formula xe2x80x94CHR1R2 wherein R1 and R2 independently or collectively represent hydrogens or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent(s), or any combination thereof, which substituent(s) can again be functionally substituted or unsubstituted; in the presence of (3) a suitable acid.
In an alternative embodiment, the process of the present invention comprises reacting at least one nitrile, including that having the generic formula (II) as defined above, with a reagent comprising both (i) at least one suitable alkoxy functionality (III), as defined above; and (ii) at least one suitable acid functionality. To this end, there are numerous classes of compounds that combine the properties of both an alkoxy-containing compound and a suitable acid.
An example of such a preferred class of compounds according to the present invention includes, without limitation, alkyl sulfates, e.g., monoalkylsulfates such as, methylsulfuric acid, ethylsulfuric acid, butylsulfuric acid and the like, having the generic formula (IV):
Xxe2x80x94CH2xe2x80x94Oxe2x80x94SO2OHxe2x80x83xe2x80x83(IV)
wherein X is a hydrogen or a radical having the general formula xe2x80x94CHR1R2 wherein R1 and R2 independently or collectively represent hydrogens or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent(s), or any combination thereof, which substituent(s) can also be functionally substituted or unsubstituted
Another example of a class of compounds comprising both (i) at least one suitable alkoxy functionality (III), as defined above; and (ii) at least one suitable acid functionality includes, without limitation, acid alkyl phosphates. For example, monoalkyl phosphates; dialkyl phosphates; mono, di, and trialkyl pyrophosphates; and mono-, di-, tri, and polyalkyl polyphosphates and the like comprising at least one alkoxy functionality of the generic formula XCH2xe2x80x94Oxe2x80x94 and one or more acid phosphate functionalities of the generic formula (V): 
In accordance with this embodiment, X again represents either a hydrogen or a radical having the general formula xe2x80x94CHR1R2 wherein R1 and R2 independently or collectively represent hydrogens or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent(s), or any combination thereof, which substituent(s) can be functionally substituted or unsubstituted.
To this end, it should be understood that the process of the present invention encompasses any appropriate combination for reacting two or more reagents independently or collectively comprising at least one suitable nitrile functionality, at least one suitable alkoxy functionality, and at least one suitable acid functionality in an environment suitable to provide a desired n-monosubstituted amide, cyclic amide (lactam), and/or polyamide. Furthermore, in accordance with several embodiments of the present invention, when one or more reactant(s) provides more than one of the necessary functionalities, e.g., nitrile, alkoxy, and/or acid, it should also be understood that the third reactant can still be present but is not required in order to effectively practice the process of the present invention. For example, in the case of a monoalkylsulfate being reacted with a suitable nitrile, the monoalkylsulfate comprises both an alkoxy and an acid functionality and, as such, a separate acid reagent and/ or a separate alkoxy reagent can be introduced into the reaction environment but is not required in order to successfully practice the invention.
In another aspect of N-monosubstituted amide group formation, the present invention further provides a process for obtaining cyclic amides, or lactams. In accordance with this aspect, when a single reagent provides at least one suitable nitrile functionality and at least one suitable alkoxy functionality, an intramolecular reaction may be provided in the presence of a suitable acid under conditions suitable to provide a cyclic amide or lactam.
In yet another aspect, the present invention also provides a process for obtaining functionally substituted amides and polyamides. For example, in one embodiment, when a single reagent provides at least one suitable nitrile functionality and at least one suitable alkoxy functionality, an intermolecular reaction may be provided in the presence of a suitable acid under conditions effective to provide, e.g., a cyano hydroxy amide, a cyano hydroxy diamide, or a cyano hydroxy polyamide.
In still another aspect, the process of amide formation according to the present invention comprises contacting one or more reagents having at least two suitable nitrile functionalities with one or more reagents comprising at least two suitable alkoxy functionalities. In accordance with this aspect of the invention, an intermolecular reaction may be provided in the presence of a suitable acid under conditions effective to provide, e.g., a cyano hydroxy amide, a cyano hydroxy diamide, a dicyano diamide, a dihydroxy diamide, a cyano hydroxy polyamide, a dicyano polyamide, a dihydroxy polyamide, and/or a cyclic polyamide.
According to the invention, a wide variety of inorganic and/or organic, Bronsted or Lewis acids can be used in this process. Furthermore, these acids can be used in their concentrated or diluted forms.
Examples of suitable Bronsted acids include, but are not limited to: sulfuric acid, fuming sulfuric acid, methylsulfuric acid or monomethyl sulfate, phosphoric acid, pyrophosphoric acid, polyphosphoric acid, chlorosulfonic acid, methane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzene disulfoacid, and trifluoromethylsulfonic acid.
Examples of suitable Lewis acids include, but are not limited to: sulfur trioxide or its complexes, boron trifluoride, aluminum chloride, aluminum bromide, and the like.
Suitable compounds comprising at least one alkoxy functionality of formula (III) as previously defined herein include without limitation, primary alcohols, such as methanol, ethanol, n-propanol, 1-butanol, 2-methyl-l-propanol, and dodecanol; glycols, such as ethylene glycol; di-, tri-, and polyglycols, such as diethylene glycol and/or polyethylene glycol; monoalkyl ethers of glycols, such as methylcellosolve; esters and orthoesters, such as dimethyl carbonate, ethyl formate, methyl acetate, diethyl malonate, and methylacetoacetate; alkyl orthocarbonates, such as methyl orthocarbonate; mono, di and tri alkyl carbonates, such as dimethyl carbonate; mono, di, and tri alkyl borates, such as trimethyl borate; mono, di and tri alkoxy silanes, such as tetraethoxysilane; alkyl orthosilicates, such as ethylorthosilicate; mono, di, tri and tetra alkoxy titanium compounds, such as tetraethoxy titanium; alkyl orthotitanates, such as methyl, ethyl, propyl or butyl ortho titanate; acid alkyl phosphates; mono, di and tri alkyl phosphates, such as trimethyl phosphate; mono, di and tri alkyl pyrophosphates, such as dimethyl pyrophosphate; alkyl polyphosphates; dialkyl sulfates, such as dimethylsulfate; alkyl sulfates, such as mono methyl, ethyl, propyl or butyl sulfate; alkyl halo sulfates, such as alkyl chlorosulfates and alkyl bromosulfates; alkyl mesylates; alkyl aryl sulfonates; ethers and dialkyl ethers, such as methyl ether and butyl ether; glycol ethers; aryl alkyl ethers; acetals, ketals, dialkyl acetals and dialkyl ketals, such as dimethoxymethane; alkyl esters, and any functionally substituted primary alcohols, glycols, esters, orthoesters, acetals or ketals.
To this end, it should be understood that any alkoxy containing compound suitable for amide formation can be used in the process of the present invention, provided that said compound comprises at least one suitable alkoxy functionality of the generic formula (III):
xe2x80x94Oxe2x80x94CH2xe2x80x94Xxe2x80x83xe2x80x83(III)
wherein X is a hydrogen or a radical having the general formula xe2x80x94CHR1R2 wherein R1 and R2 independently or collectively represent hydrogens or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent(s), or any combination thereof, which substituent(s) can be functionally substituted or unsubstituted. Furthermore, it should also be understood that additional alkoxy containing compounds suitable for amide formation, others than those set forth in detail above, will be recognized by those of ordinary skill in the art or otherwise determined through mere routine experimentation.
Additionally, as set forth above, suitable nitriles for use in the process of the present invention included any compound having the generic formula (II):
Rxe2x80x94CNxe2x80x83xe2x80x83(II)
wherein R is a hydrogen or any alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, which substituents can be substituted or unsubstituted. For example, preferred nitrites for use in the process of the present invention include both hydroxy nitrites and alkoxy nitrites; acetonitrile; propionitrile; 2,3-dimethyl-2-(1xe2x80x2-methylethyl) butanenitrile; p-menthanecarbonitrile; and benzonitrile. To this end, it should be understood that additional nitrites suitable for amide formation, other than those set forth in detail above, will be recognized by those of ordinary skill in the art or otherwise determined through mere routine experimentation.
It is also contemplated by the present invention that there are numerous cases when contacting an alkoxy-containing compound with an acid will produce a second alkoxy-containing compound and a second acid. Accordingly, in another aspect of the present invention, one or more of the desired reagents, e.g., the alkoxy-containing compound, is (are) formed in the reaction mixture in situ.
For example, an alkyl mesylate can be obtained in situ by contacting methanesulfochloride with an alkanol. Alternatively, an alkyl chlorosulfate can be obtained in situ by contacting chlorosulfonic acid with an alkanol. Likewise, a dialkyl ether can react with sulfuric acid to provide a monoalkyl sulfate and an alkanol. Similarly, dialkyl sulfate can react with sulfuric acid to provide a monoalkyl sulfate. Furthermore, a trialkyl phosphate can react with a polyphosphoric acid to provide a mixture of acid alkyl phosphates and polyphosphates.
It is also known that alkyl groups can reversibly migrate to sulfuric acid from trialkyl borates or trialkyl phosphates to provide monoalkyl sulfates and partial (acid) esters of boric or phosphoric acid. Alternatively, a dialkyl carbonate can react with sulfuric acid to provide monoalkyl sulfate, alcohol and carbon dioxide. Furthermore, it is also known that alcohols can react with sulfur trioxide to provide monoalkyl sulfates.
Accordingly, depending on the addition sequence and the reaction conditions, it is contemplated by the present invention that such reactions can occur in the presence of a nitrite, before the addition of a nitrite, and/or during the addition of nitrile into the reaction environment. Consequently, in alternative embodiments of the present invention, a nitrile can react with an originally charged alkoxy-containing compound and acid or with a subsequently formed alkoxy-containing compound and acid.
In still a further embodiment of the present invention, it is contemplated that, depending on the reaction conditions, the desired N-monosubstituted amide can either be present in the reaction mixture as a final product, or it can be present in the form of an intermediate complex. In those instances where the desired amide forms as an intermediate reaction complex, a hydrolytic or solvolytic work up may be necessary to recover the product from the reaction mixture.
According to the invention, a hydrolytic or solvolytic workup includes, but is not limited to, treatment with water, aqueous solutions of bases or acids, treatment with alcohols, or any other treatment that aids in and/or results in the recovery of the desired amide from the reaction mixture.
The process of the present invention can also be performed over a wide variety of conditions. Additionally, the process of the present invention can also be performed either continuously or batch-wise. Although the reaction generally proceeds regardless of the temperature, addition sequence, addition rates, and the ratio of the reagents, all these and other parameters can be optimized in order to obtain higher yields of N-monosubstituted amides. Such optimization parameters will be recognized by one of ordinary skill in the art or otherwise achieved through routine experimentation.
The reaction temperature may vary within a wide range, and may even vary during the process, or during different steps of the process. For example, the process can proceed at temperatures of xe2x88x9220xc2x0 C., xe2x88x9210xc2x0 C., 0xc2x0 C., 10xc2x0 C., 20xc2x0 C., 30xc2x0 C., 40xc2x0 C., 50xc2x0 C., 60xc2x0 C., 70xc2x0 C., 80xc2x0 C., 90xc2x0 C., 100 xc2x0 C., 110xc2x0 C., 120xc2x0 C., 130xc2x0 C., 140xc2x0 C., 150xc2x0 C., 160xc2x0 C., 170xc2x0 C., 180xc2x0 C., 190xc2x0 C., 200xc2x0 C., 210xc2x0 C., 220xc2x0 C., 230xc2x0 C., 240xc2x0 C., or even 250xc2x0 C. In a preferred embodiment, the temperature is not lower than about xe2x88x9220xc2x0 C. Moreover, the temperature is preferably not greater than about 250xc2x0 C. More preferably, the temperature is not less than about 25xc2x0 C. and not greater than about 180xc2x0 C.
According to the invention, the process can be performed under varying degrees of pressure and reaction time. For example, the process is effective under atmospheric pressure, under increased pressure, or even under vacuum. To this end, the optimum amount of pressure and reaction time will, of course, vary depending on the particular reactants used and will further be recognized by one of ordinary skill in the art or otherwise determined through routine experimentation.
The process can also successfully proceed under varying molar ratios of alkoxy containing compound to nitrile. In a preferred embodiment, the process is preferably performed with a molar ratio of alkoxy-containing compound to nitrile of from about 0.1 to about 50. For example, the ratio of alkoxy-containing compound to nitrile can be 0.1, 0.3, 0.5, 0.7, 0.9, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or even 50. In a more preferred embodiment, from about 0.3 to about 10, and even more preferably from about 0.5 to about 5.
The process can also successfully proceed with varying molar ratios of acid to nitrile. In a preferred embodiment, the molar ratio of acid to nitrile is from about 0.01 to about 100. In accordance with this embodiment, the molar ratio of acid to nitrile can be 0.01, 0.05, 0.1, 0.5, 1.0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or even 100. In a more preferred embodiment, the molar ration of acid to nitrile is from about 0.5 to about 10. Alternatively, in a most preferred embodiment, the ratio of acid to nitrile is from about 1 to about 5.
The process of the present invention can also be successfully performed in the presence of an organic or inorganic solvent, or even without a solvent. Examples of suitable solvents include, without limitation, alkanes, chloro- and polychloroalkanes, formamides, and combinations thereof. When the reaction is carried out using an excess of one of the reagents, erg., a nitrile, an alkoxy-containing compound, or an acid, the excess reagent can also serve as the solvent
When the present process is performed batchwise, various modes or sequences of addition/mixing of reagents can be used, for example:
1) addition of an alkoxy-containing compound and a solvent into a mixture of a nitrile, acid and another solvent, or optionally, the same sequence without one or both solvents;
2) simultaneous mixing of an acid, a nitrile, an alkoxy-containing compound, and a solvent, or, optionally, the same sequence without the solvent;
3) premixing an acid and an alkoxy-containing compound, with or without a solvent, followed by addition of a nitrile, also with or without a solvent;
4) addition of an acid to a mixture of a nitrile, an alkoxy-containing compound, and an optional solvent.
Similarly, when the process is carried out in a continuous manner, the reagents and optional solvents can be fed into a reactor or reaction environment simultaneously or in any order.
In those embodiments where one or more of the reagents provide two or more functional groups, e.g., a monoalkyl sulfate which provides both an acid and alkoxy functionality, the reagents and optional solvents can also be mixed or fed in any order.
To this end, the process of present invention encompasses any appropriate sequence of addition and/or mixing of two or more appropriate reagents, with or without one or more solvents, in an environment suitable to provide a desired, n-monosubstituted amide, cyclic amide (lactam), and/or functionally substituted di- or polyamide. Furthermore, it should also be understood that, in each case, the optimum sequence of mixing depends on the nature of the starting materials and the solvent used. Accordingly, the optimal sequences will be recognized by those of ordinary skill in the art or otherwise determined through routine experimentation.
After completion of the reaction, the reaction mixture can be worked up in many ways. For example, in an embodiment comprising a hydrolytic work up, the product mixture can be xe2x80x9cquenchedxe2x80x9d with water or an aqueous base, or poured onto ice and neutralized with an aqueous base, then extracted with a solvent. After evaporation of the solvent, the product can be distilled and/or crystallized.
In an embodiment comprising a solvolytic work up, the reaction mixture can be diluted, for example, with an excess of a lower alcohol (methanol, ethanol, etc.), and the product can be crystallized from its alcohol solution, or separated in any other way known in the art. In some cases, the reaction mixture can also be directly distilled to give the desirable product, and in other cases, the product can be obtained from the reaction mixture by direct crystallization followed by an optional purification.
Thus, the present invention is capable of providing a convenient and highly practical process for obtaining desired N-monosubstituted amides, cyclic amides (lactams), functionally substituted di- or polyamides, and cyclic polyamides, by contacting corresponding nitrites with corresponding alkoxy-containing compounds and acids. Additional advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.